Class IA Phosphoinositide 3-Kinase Modulates Basal Lymphocyte Motility in the Lymph Node

Matheu, Melanie P.; Deane, Jonathan A.; Parker, Ian; Fruman, David A.; Cahalan, Michael D.

doi:10.4049/jimmunol.179.4.2261

Cited by 37 publications

(42 citation statements)

References 43 publications

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“…The discrepancy to other published reports 32,33 is unclear at the moment but could be the result of different transgenic models. Although PI3K␦ activity is required for full ERK phosphorylation downstream TCR signaling, 61,62 expression of inactive PI3K␦ did not reduce CCL21-mediated costimulation in the experimental model used here. PI3K activity thus appears dispensable for CCL21-mediated costimulation in vitro.…”

Section: Discussionmentioning

confidence: 60%

CCL21 mediates CD4+ T-cell costimulation via a DOCK2/Rac-dependent pathway

Gollmer

Asperti-Boursin

Tanaka

et al. 2009

Blood

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CD4 ؉ T cells use the chemokine receptor CCR7 to home to and migrate within lymphoid tissue, where T-cell activation takes place. Using primary T-cell receptor (TCR)-transgenic (tg) CD4 ؉ T cells, we explored the effect of CCR7 ligands, in particular CCL21, on T-cell activation. We found that the presence of CCL21 during early time points strongly increased in vitro T-cell proliferation after TCR stimulation, correlating with increased expression of early activation markers. CCL21 costimulation resulted in increased Rasand Rac-GTP formation and enhanced phosphorylation of Akt, MEK, and ERK but not p38 or JNK. Kinase-dead PI3K␦ D910A/D910A or PI3K␥-deficient TCR-tg CD4 ؉ T cells showed similar responsiveness to CCL21 costimulation as control CD4 ؉ T cells. Conversely, deficiency in the Rac guanine exchange factor DOCK2 significantly impaired CCL21-mediated costimulation in TCR-tg CD4 ؉ T cells, concomitant with impaired Rac-but not Ras-GTP formation. Using lymph node slices for live monitoring of T-cell behavior and activation, we found that G proteincoupled receptor signaling was required for early CD69 expression but not for Ca 2؉ signaling. Our data suggest that the presence of CCL21 during early TCR signaling lowers the activation threshold through Ras-and Rac-dependent pathways leading to increased ERK phosphorylation. (Blood. 2009;114:580-588) IntroductionNaive T cells continuously traffic to secondary lymphoid organs, including peripheral lymph nodes (PLNs), where they screen antigen-presenting cells (APCs), in particular dendritic cells (DCs), for the presence of specific peptide Ag presented on MHC (pMHC) complexes. 1 In proinflammatory conditions, DCs expressing cognate pMHC and costimulatory signals, such as B7 molecules, induce efficient T-cell activation through the T-cell receptor (TCR) and CD28. 2 This leads to an early signaling response characterized by activation of multiple signaling pathways, including tyrosine kinase cascades, sustained increase in intracellular Ca 2ϩ , and activation of phosphoinositide-3-kinase (PI3K), small GTPases of the Ras and Rho family, mitogen-activated protein kinase, nuclear factor of activated T-cell, and nuclear factor-B. Activated T cells subsequently increase surface expression of early activation markers, such as CD69 and CD25, produce interleukin-2 (IL-2), expand clonally, and differentiate into effector cells.Direct observations of lymphocytes and DCs presenting cognate pMHC complexes in explanted PLNs or live mice using 2-photon microscopy have uncovered a dynamic range of cellular interactions within lymphoid tissue. In some settings, T cells almost immediately arrest on encountering DCs. 3 Alternatively, T cells were observed to continue to migrate during the first several hours after entry into lymphoid tissue along the stromal network formed by fibroblastic reticular cells (FRCs), where they underwent brief serial contacts with DCs. 4 This first phase of high motility is reminiscent of naive T-cell migration in the absence of pMHC-loaded DCs. 4,5 Of not...

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Section: Discussionmentioning

confidence: 60%

CCL21 mediates CD4+ T-cell costimulation via a DOCK2/Rac-dependent pathway

Gollmer

Asperti-Boursin

Tanaka

et al. 2009

Blood

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“…In lymph node slices imaged by epifluorescence microscopy, pretreatment with wortmannin had no effect on T cell motility (57). In contrast, recent work from our group, in collaboration with David Fruman (70), showed that wortmannin treatment resulted in a significant decrease in T and B cell motility in lymph node explants ( Table 2). Although class IA and IB catalytic subunits (p110δ and p110γ, respectively) had previously been shown to be involved in lymphocyte chemotaxis and homing (71,72), and p110γ is indispensable for neutrophil chemotaxis (73-75), p110γ deletion had only a minor effect on T cell motility and did not alter velocity or B cell motility (76).…”

Section: Than In T Cells (66)mentioning

confidence: 89%

Choreography of Cell Motility and Interaction Dynamics Imaged by Two-Photon Microscopy in Lymphoid Organs

Cahalan

Parker

2008

Annu. Rev. Immunol.

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287

280

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The immune system is the most diffuse cellular system in the body. Accordingly, long-range migration of cells and short-range communication by local chemical signaling and by cell-cell contacts are vital to the control of an immune response. Cellular homing and migration within lymphoid organs, antigen recognition, and cell signaling and activation are clearly vital during an immune response, but these events had not been directly observed in vivo until recently. Introduced to the field of immunology in 2002, two-photon microscopy is the method of choice for visualizing living cells deep within native tissue environments, and it is now revealing an elegant cellular choreography that underlies the adaptive immune response to antigen challenge. We review cellular dynamics and molecular factors that contribute to basal motility of lymphocytes in the lymph node and cellular interactions leading to antigen capture and recognition, T cell activation, B cell activation, cytolytic effector function, and antibody production.

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“…This effect does not appear to be subset restricted, as both CD4 + and CD8 + memory T cells display similar requirements for p110δ activity to be recruited in an antigen-dependent manner. In this context, class I PI3K regulatory subunit p85 has been shown to contribute to spontaneous lymphocyte motility in the lymph node (18). As PI3Ks have been implicated in signaling pathways leading to integrin activation, it is possible that p85 activity may be required for efficient cell-cell interactions in the lymph nodes.…”

Section: Discussionmentioning

confidence: 99%

T cell receptor–induced phosphoinositide-3-kinase p110δ activity is required for T cell localization to antigenic tissue in mice

Jarmin¹,

David²,

Ma³

et al. 2008

J. Clin. Invest.

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The establishment of T cell-mediated inflammation requires the migration of primed T lymphocytes from the blood stream and their retention in antigenic sites. While naive T lymphocyte recirculation in the lymph and blood is constitutively regulated and occurs in the absence of inflammation, the recruitment of primed T cells to nonlymphoid tissue and their retention at the site are enhanced by various inflammatory signals, including TCR engagement by antigen-displaying endothelium and resident antigen-presenting cells. In this study, we investigated whether signals downstream of TCR ligation mediated by the phosphoinositide-3-kinase (PI3K) subunit p110δ contributed to the regulation of these events. T lymphocytes from mice expressing catalytically inactive p110δ displayed normal constitutive trafficking and migratory responses to nonspecific stimuli. However, these cells lost susceptibility to TCR-induced migration and failed to localize efficiently to antigenic tissue. Importantly, we showed that antigen-induced T cell trafficking and subsequent inflammation was abrogated by selective pharmacological inhibition of PI3K p110δ activity. These observations suggest that pharmacological targeting of p110δ activity is a viable strategy for the therapy of T cell-mediated pathology.

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Class IA Phosphoinositide 3-Kinase Modulates Basal Lymphocyte Motility in the Lymph Node

Cited by 37 publications

References 43 publications

CCL21 mediates CD4+ T-cell costimulation via a DOCK2/Rac-dependent pathway

CCL21 mediates CD4+ T-cell costimulation via a DOCK2/Rac-dependent pathway

Choreography of Cell Motility and Interaction Dynamics Imaged by Two-Photon Microscopy in Lymphoid Organs

T cell receptor–induced phosphoinositide-3-kinase p110δ activity is required for T cell localization to antigenic tissue in mice

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